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13 results on '"Grebliunaite, Ruta"'

1. Aberrant AKT activation drives well-differentiated liposarcoma

Author

Gutierrez, Alejandro, Snyder, Eric L., Marino-Enriquez, Adrian, Zhang, Yi-Xiang, Sioletic, Stefano, Kozakewich, Elena, Grebliunaite, Ruta, Ou, Wen-bin, Sicinska, Ewa, Raut, Chandrajit P., Demetri, George D., Perez-Atayde, Antonio R., Wagner, Andrew J., Fletcher, Jonathan A., Fletcher, Christopher D. M., and Look, A. Thomas

Published
2011

2. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

Author

Gutierrez, Alejandro, Pan, Li, Groen, Richard W.J., Baleydier, Frederic, Kentsis, Alex, Marineau, Jason, Grebliunaite, Ruta, Kozakewich, Elena, Reed, Casie, Pflumio, Francoise, Poglio, Sandrine, Uzan, Benjamin, Clemons, Paul, VerPlank, Lynn, An, Frank, Burbank, Jason, Norton, Stephanie, Tolliday, Nicola, Steen, Hanno, Weng, Andrew P., Yuan, Huipin, Bradner, James E., Mitsiades, Constantine, Look, A. Thomas, and Aster, Jon C.

Subjects
T cells -- Physiological aspects -- Research, Phenothiazine -- Dosage and administration -- Research, Phosphatases -- Research, Acute lymphocytic leukemia -- Care and treatment -- Research, Apoptosis -- Research, Health care industry
Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential., Introduction T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer affecting mainly adolescents and young adults. Intensified treatment regimens have improved outcomes, but patients who fail conventional therapy have [...]

Published
2014
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3. Inactivation of LEF1 in T-cell acute lymphoblastic leukemia

Author

Gutierrez, Alejandro, Sanda, Takaomi, Ma, Wenxue, Zhang, Jianhua, Grebliunaite, Ruta, Dahlberg, Suzanne, Neuberg, Donna, Protopopov, Alexei, Winter, Stuart S., Larson, Richard S., Borowitz, Michael J., Silverman, Lewis B., Chin, Lynda, Hunger, Stephen P., Jamieson, Catriona, Sallan, Stephen E., and Look, A. Thomas

Published
2010
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4. Abstract IA8: A new class of drugs active in T-ALL is revealed in a zebrafish screen

Author

Gutierrez, Alejandro, primary, Pan, Li, additional, Groen, Richard, additional, Baleydier, Frederic, additional, Kentsis, Alex, additional, Marineau, Jason, additional, Grebliunaite, Ruta, additional, Kozakewich, Elena, additional, Reed, Casie, additional, Pflumio, Francoise, additional, Poglio, Sandrine, additional, Uzan, Benjamin, additional, Clemons, Paul, additional, Verplank, Lynn, additional, An, Frank, additional, Burbank, Jason, additional, Norton, Stephanie, additional, Tolliday, Nicola, additional, Steen, Hanno, additional, Weng, Andrew P., additional, Yuan, Huipin, additional, Bradner, James E., additional, Mitsiades, Constantine, additional, Look, A. Thomas, additional, and Aster, Jon C., additional

Published
2014
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5. Aberrant AKT activation drives well-differentiated liposarcoma

Author

Koch Institute for Integrative Cancer Research at MIT, Snyder, Eric, Gutierrez, Alejandro, Marino-Enriquez, Adrian, Zhang, Yi-Xiang, Sioletic, Stefano, Kozakewich, Elena, Grebliunaite, Ruta, Ou, Wen-bin, Sicinska, Ewa, Raut, Chandrajit P., Demetri, George D., Perez-Atayde, Antonio R., Wagner, Andrew J., Fletcher, Jonathan A., Fletcher, Christopher D. M., Look, A. Thomas, Koch Institute for Integrative Cancer Research at MIT, Snyder, Eric, Gutierrez, Alejandro, Marino-Enriquez, Adrian, Zhang, Yi-Xiang, Sioletic, Stefano, Kozakewich, Elena, Grebliunaite, Ruta, Ou, Wen-bin, Sicinska, Ewa, Raut, Chandrajit P., Demetri, George D., Perez-Atayde, Antonio R., Wagner, Andrew J., Fletcher, Jonathan A., Fletcher, Christopher D. M., and Look, A. Thomas

Abstract

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1106127108/-/DCSupplemental., Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma., Ludwig Center at Dana-Farber/Harvard Cancer Center and Harvard Medical School, Harvard Catalyst, National Institutes of Health (U.S.) (Award UL1 RR 025758), Harvard University, National Institutes of Health (U.S.) (Grant 1K08CA133103), Fundación Alfonso Martín Escudero

Published
2012

7. Phenothiazines Induce Apoptosis in T-Cell Acute Lymphoblastic Leukemia by Activating the Phosphatase Activity of the PP2A Tumor Suppressor

Author

Gutierrez, Alejandro, primary, Kentsis, Alex, additional, Pan, Li, additional, Baleydier, Frederic, additional, Marineau, Jason, additional, Grebliunaite, Ruta, additional, Kozakewich, Elena, additional, Reed, Casie, additional, Pflumio, Francoise, additional, Poglio, Sandrine, additional, Uzan, Benjamin, additional, Clemons, Paul A., additional, VerPlank, Lynn, additional, An, W. Frank, additional, Burbank, Jason, additional, Norton, Stephanie, additional, Tolliday, Nicola J, additional, Steen, Hanno, additional, Bradner, James E, additional, Look, A. Thomas, additional, and Aster, Jon C, additional

Published
2012
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8. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

Author

Gutierrez, Alejandro, primary, Grebliunaite, Ruta, additional, Feng, Hui, additional, Kozakewich, Elena, additional, Zhu, Shizhen, additional, Guo, Feng, additional, Payne, Elspeth, additional, Mansour, Marc, additional, Dahlberg, Suzanne E., additional, Neuberg, Donna S., additional, den Hertog, Jeroen, additional, Prochownik, Edward V., additional, Testa, Joseph R., additional, Harris, Marian, additional, Kanki, John P., additional, and Look, A. Thomas, additional

Published
2011
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9. Absence of Biallelic TCRγ Deletion Predicts Early Treatment Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia

Author

Gutierrez, Alejandro, primary, Dahlberg, Suzanne E., additional, Neuberg, Donna S., additional, Zhang, Jianhua, additional, Grebliunaite, Ruta, additional, Sanda, Takaomi, additional, Protopopov, Alexei, additional, Tosello, Valeria, additional, Kutok, Jeffery, additional, Larson, Richard S., additional, Borowitz, Michael J., additional, Loh, Mignon L., additional, Ferrando, Adolfo A., additional, Winter, Stuart S., additional, Mullighan, Charles G., additional, Silverman, Lewis B., additional, Chin, Lynda, additional, Hunger, Stephen P., additional, Sallan, Stephen E., additional, and Look, A. Thomas, additional

Published
2010
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10. Absence of T-Cell Receptor Gene Rearrangements Predicts Induction Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Author

Gutierrez, Alejandro, primary, Grebliunaite, Ruta, additional, Dahlberg, Suzanne E., additional, Neuberg, Donna, additional, Zhang, Jianhua, additional, Sanda, Takaomi, additional, Protopopov, Alexei, additional, Chin, Lynda, additional, Winter, Stuart, additional, Larson, Richard S., additional, Kutok, Jeffery Lorne, additional, Silverman, Lewis B., additional, Hunger, Stephen P, additional, Sallan, Stephen E., additional, and Look, A. Thomas, additional

Published
2009
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11. Inactivation of LEF1in T-cell acute lymphoblastic leukemia

Author

Gutierrez, Alejandro, Sanda, Takaomi, Ma, Wenxue, Zhang, Jianhua, Grebliunaite, Ruta, Dahlberg, Suzanne, Neuberg, Donna, Protopopov, Alexei, Winter, Stuart S., Larson, Richard S., Borowitz, Michael J., Silverman, Lewis B., Chin, Lynda, Hunger, Stephen P., Jamieson, Catriona, Sallan, Stephen E., and Look, A. Thomas

Abstract

To further unravel the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), we performed high-resolution array comparative genomic hybridization on diagnostic specimens from 47 children with T-ALL and identified monoallelic or biallelic LEF1microdeletions in 11% (5 of 47) of these primary samples. An additional 7% (3 of 44) of the cases harbored nonsynonymous sequence alterations of LEF1, 2 of which produced premature stop codons. Gene expression microarrays showed increased expression of MYCand MYC targets in cases with LEF1inactivation, as well as differentiation arrest at an early cortical stage of thymocyte development characterized by expression of CD1B, CD1E, and CD8, with absent CD34 expression. LEF1inactivation was associated with a younger age at the time of T-ALL diagnosis, as well as activating NOTCH1mutations, biallelic INK4a/ARFdeletions, and PTENloss-of-function mutations or activating mutations of PI3Kor AKTgenes. These cases generally lacked overexpression of the TAL1, HOX11, HOX11L2, or the HOXAcluster genes, which have been used to define separate molecular pathways leading to T-ALL. Our findings suggest that LEF1inactivation is an important step in the molecular pathogenesis of T-ALL in a subset of young children.

Published
2010
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12. High frequency of PTEN, PI3K, and AKTabnormalities in T-cell acute lymphoblastic leukemia

Author

Gutierrez, Alejandro, Sanda, Takaomi, Grebliunaite, Ruta, Carracedo, Arkaitz, Salmena, Leonardo, Ahn, Yebin, Dahlberg, Suzanne, Neuberg, Donna, Moreau, Lisa A., Winter, Stuart S., Larson, Richard, Zhang, Jianhua, Protopopov, Alexei, Chin, Lynda, Pandolfi, Pier Paolo, Silverman, Lewis B., Hunger, Stephen P., Sallan, Stephen E., and Look, A. Thomas

Abstract

To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKTwere identified in 47.7% of 44 cases. There was a striking clustering of PTENmutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTENdeletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTENexon 7 (P= .007), suggesting that PTENdeletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.

Published
2009
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13. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia.

Author

Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F, Payne E, Mansour M, Dahlberg SE, Neuberg DS, den Hertog J, Prochownik EV, Testa JR, Harris M, Kanki JP, and Look AT

Subjects
Animals, Animals, Genetically Modified, Apoptosis genetics, Blotting, Western, Cryoultramicrotomy, DNA Primers genetics, Immunohistochemistry, In Situ Hybridization, PTEN Phosphohydrolase genetics, Reverse Transcriptase Polymerase Chain Reaction, Tamoxifen analogs & derivatives, Zebrafish, Gene Expression Regulation, Neoplastic genetics, PTEN Phosphohydrolase metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-myc metabolism, Signal Transduction genetics
Abstract

The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.

Published
2011
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